DESCRIPTION: SHIV macaque models provide an important benchmark for pre-clinical HIV-1 research, serving as a gatekeeper for advancing vaccine and other prevention approaches. The ability of such models to predict intervention(s) that will be efficacious in humans depends to a large extent on how faithfully the model recapitulates key features of HIV-1 transmission and pathogenesis in humans, including both sexual and parenteral transmission. To date, SHIVs have largely been selected by trial and error using the most readily available HIV-1 variants, often those that have been adapted to replication in cell culture (lab-adapted HIV-1 variants). As a result, few SHIV models incorporate key features of circulating variants that are the target of vaccine and other prevention methods. Although efforts in this area are increasing, approaches nonetheless generally rely on constructing and testing a series of SHIV chimeras encoding available HIV-1 variants and moving forward the one that replicates best. Of note, this process of generating pathogenic SHIVs includes serial passage of the virus in macaques to further increase replication fitness, and all of the SHIVs in current use have been adapted in this manner (adapted SHIVs). We propose to pioneer a rational design approach to developing relevant SHIVs that better represent circulating HIV-1 variants central to the pandemic. We have found several barriers to HIV-1 replication in macaque cells that are specific to transmitted/founder (T/F) viruses circulating in humans. These restrictions do not appear to be the result of known restriction factors, which are generally not specific to select HIV-1 variants. In our preliminary studies, we found that IFN-stimulated responses have a pronounced effect on the replication of SHIVs encoding circulating T/F envelope variants in macaque T cells, but not on adapted SHIVs. Another critical species-specific barrier of HIV-1s circulating in humans is the macaque CD4 receptor, which is generally a poor receptor for T/F variants, but a functional receptor for lab-adapted variants, potentially explaining the bias towards developing SHIVs based on lab-adapted HIV-1 variants. While T/F variants can be adapted to use the macaque CD4 receptor, adaptation leads to antigenic changes that alter recognition of several broad NAbs that are currently the centerpiece of HIV-1 vaccine efforts. Here, we propose to exploit these preliminary findings to define the mechanisms underlying the envelope-mediated restrictions to HIV-1 replication in macaques, to define the consequences of these changes for the utility of the model and to identify pathways to developing rationally designed SHIVs with enhanced utility for preclinical studies of HIV-1 vaccine and prevention methods.